The present invention relates generally to methods and compositions for killing ectoparasites.
Head lice infestation is a persistent problem with as many as 6-12 million people worldwide affected each year. The problem is particularly prevalent in children with preschool and elementary-age children aged 3-10 and their families becoming infested most often. Head lice infestation is produced by the common head louse Pediculus humanus capitis, and typically causes itching of the scalp. As the lice feed on human blood, they may cause lesions to develop on the scalp, swollen glands on the neck or under arms, or other symptoms. Head lice infestation causes serious problems due to the negative social implications of the infestation. Body lice are also bothersome to humans and carry the additional hazard of being the vectors of certain diseases, such as exanthematic or epidemic typhus and recurrent fever.
Various compositions are available for treating these infestations, which generally take a topical approach to treatment. Most of these treatments involve the use of insecticides that are harsh agents, thus raising toxicity concerns. The lice can also become resistant to the insecticides used and therefore the compositions can lose their effectiveness over time.
The present invention provides compositions and methods for killing ectoparasites on a subject. In the most preferred embodiments, the subject is a human and the ectoparasites are lice, fleas, and ticks. In one embodiment, the compositions contain a fatty acid ester in an amount sufficient for killing lice, and the fatty acid ester is present as the sole agent effective for such treatment. In one embodiment, the fatty acid ester is an ester of myristate, e.g., isopropyl myristate. In another embodiment, the composition may also contain a siloxane, e.g., deca-cyclomethicone (silicone). And in a most preferred embodiment, the composition contains both isopropyl myristate and decacyclomethicone and does not contain any other agent in an amount sufficient for killing ectoparasites. In other embodiments, the compositions may also contain a mectin (such as ivermectin) and/or a mycin (such as milbemycin). In further embodiments, the compositions also contain sesquiterpenes, such as S-methoprene, which is effective for killing the eggs of ectoparasites, or juvenile hormone analogs (e.g., hydroprene, fenoxycarb and pyriproxyfen).
In a preferred embodiment, the compositions are formulated to be applied to the scalp of a person suffering from a head lice infestation and are left on the treated person for a period of time. The compositions are preferably left on the treated area for about 5-15 minutes, and more preferably for about 10 minutes, with the effect of killing lice and their eggs present within 1 hour or less. In other aspects the compositions, methods, and uses are effective for treating domestic pets for flea infestation or for treating insect infestation of crops.
The term xe2x80x9csubjectxe2x80x9d includes humans, plants, and mammals. The term xe2x80x9cmammalxe2x80x9d includes humans, and also includes animals that are members of the class Mammalia. This will usually be a human but also includes pets such as dogs, cats, ferrets, rabbits, gerbils, and guinea pigs. Mammals also include domestic animals such as bovines, porcines, ovines, and equines. While most fur-bearing animals can become infested with fleas and ticks, pigs, horses, and cattle can also be infested with lice (e.g., the Haematopinus suis, which infests pigs, and other Haematopinus spp. that infest horses and cattle). All of these infestations are treatable with the compositions described herein. By a topical application is meant that the composition is applied to the exterior of the treated subject, e.g. to the exterior skin,.hair, fur, or foliage. This application includes, but is not limited to, manual application or application by various automated means, for example, spraying or painting onto a treated subject, or other means. By xe2x80x9cfatty acid esterxe2x80x9d is meant an ester composed of an organic molecule bonded to a fatty acid, e.g. isopropyl myristate. Fatty acid refers to any acid derived from fats by hydrolysis and having from 6 to 22 carbon atoms. An ester is a functional derivative of a carboxylic acid, where the xe2x80x94OH group of the carboxylic acid has been replaced by an xe2x80x94OR, R being an alkyl group. By an xe2x80x9cagentxe2x80x9d is meant any compound, composition, or chemical entity. By xe2x80x9camount sufficient for killingxe2x80x9d or xe2x80x9ceffectivexe2x80x9d for killing lice or other ectoparasites is meant that at least 75% of lice or ectoparasite present are killed within 24 hours after a 10 minute exposure to the composition. In other embodiments, at least 90% or at least 95% or at least 98% or at least 99% or even 100% of the lice or ectoparasite present on the treated subject are killed within 24 hours after a 10 minute exposure to the composition. In other embodiments, the percentage of lice or other ectoparasites killed can be evaluated after 1 hour following a 10 minute exposure to the composition. In one embodiment, the in vitro test described in the Examples can be used to determine the xe2x80x9camount sufficientxe2x80x9d or whether a compound is xe2x80x9ceffective.xe2x80x9d In still further embodiments, the exposure time can be increased to achieve the percentages of lice, fleas, or other ectoparasites killed, e.g. that 95% of the ectoparasites present are killed within 24 hours after a 15 minute exposure, or a 30 minute exposure, or a 45 minute exposure. A siloxane is a compound having the Sixe2x80x94Oxe2x80x94Si bond, the main chemical bond found in silica. By xe2x80x9cinfestationxe2x80x9d is meant the presence of lice, fleas, ticks, or other ectoparasites that are the target of the treatment. Ectoparasites or pests include, but are not limited to, head lice, body lice (e.g., Pediculus humanus), crab lice (e.g., Phthirus pubis), mites (scabies), fleas and ticks. The presence of eggs of the target ectoparasite also constitutes infestation.
The methods of the present invention include topically administering a composition of the invention to an area on the mammal where ectoparasites are present. As noted above, the compositions preferably remain in contact with the treated area for a period of time. In various embodiments, no aqueous solution is applied to the treated area for at least 10 minutes or 30 minutes or 1 hour after the topical administration such as, for example, by washing the treated area. In various embodiments the mectin and/or mycin can be replaced with another compound such as pyrethroids, organophosphates such as malathion and diazinon, pyrroles, or more generally azoles, glyphosate, nicotinoids, and triazines.
Methods are also provided of manufacturing a medicament for treating ectoparasite infestation on a fur-bearing mammal. These methods involve providing a medicament containing an above-described composition. New uses of compositions are also provided. The medicaments are useful for killing fleas, lice, ticks, and other pests on a mammal and contain a composition of the present invention. The present invention also provides methods of treating ectoparasite infestation on a mammal by topically administering a composition containing ivermectin to an area on the mammal where lice, fleas, ticks or other ectoparasites are present. The composition can be any of the compositions of the present invention, or can also be ivermectin and any suitable carrier.
The summary of the invention described above is not limiting and other features and advantages of the invention will be apparent from the following detailed description of the preferred embodiments, as well as from the claims.
The present invention provides compositions that are useful for treating ectoparasites on a mammal. The present inventors discovered unexpectedly that just fatty acid esters alone, preferably isopropyl myristate, have the effect of killing ectoparasites. The present inventors also discovered unexpectedly that silicones (e.g., a cyclomethicone) also have the ability to kill ectoparasites, particularly decacyclomethicone. Thus, either or both of these may be included in a composition in an amount effective for killing lice, fleas, ticks and other ectoparasites to result in a composition that is effective for this purpose. Isopropyl myristate was found to be a particularly effective fatty acid ester. But the most preferred embodiments will include both isopropyl myristate and decacyclomethicone. These compositions offer the surprising and highly desirable combination of benefits of being highly effective, spreading evenly, drying quickly, having low mammalian toxicity, and being hair and skin compatible by not having a greasy or oily texture. Therefore the compositions eliminate the disadvantages of previously available compositions of being messy and inconvenient to apply, emitting an unpleasant odor, having limited effectiveness, or having substantial mammalian toxicity. Thus, the present compositions can thus be applied before bedtime to a human subject and, as shown in the examples herein, provide a high degree of efficacy for killing lice and other ectoparasites. Where the treated subject is a domestic animal or household pet, previously available compositions suffer from poor effectiveness, high toxicity, or are so unpleasant and cause so high a level of discomfort if applied to the coat or fur of the treated subject as to make them impractical to use with animals. The present compositions can be conveniently applied to animals and will not result in discomfort to the animal, efforts by the animal to remove the composition, or result in the animal contaminating household items with the composition, since the compositions dry quickly, spread evenly, and are of low toxicity. It is preferable that the compositions not contain any alcohols since the treated patient will have bites and lesions on the scalp or body caused by the ectoparasite, and the application of compositions containing alcohols will cause pain and discomfort. Thus, in the most preferred embodiments the compositions will not contain aliphatic alcohols or any other alcohols.
The present invention further provides the benefit of a composition that can be applied for an extended period of contact. Unlike many presently available compositions which are toxic and therefore must be washed off the treated area within minutes of application, the present compositions can be left on the treated area for periods up to several hours if desired, e.g. for 5 minutes, 10 minutes, 15 minutes, 5-15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, or even 24 hours. The compositions can be left on the treated area for periods up to several hours because of the low mammalian toxicity of the compositions of the present invention, but particularly in the case of humans, the composition is preferably left on the treated area for about 10 minutes and washed off.
Other siloxanes are also useful in the present invention. The siloxane is preferably a volatile, cyclic, non-polymeric silicone that dries quickly, spreads evenly, and does not leave a greasy residue. Examples of siloxanes that find use in various embodiments of the invention are octamethylcyclomethicone, cyclotetrasiloxane, cyclopentasiloxane, cyclohexasiloxane, polydimethyl siloxanes, polyalkylsiloxanes, polyethersiloxane copolyers, dimethicone, amodimethicones such as trimethylsilylamodimethicone, polysilanols, phenyl dimethicones, diphenyl dimethicones, dimethiconols, dimethicone copolyols, cetearyl methicones, hexamethyldisiloxanes, octamethylcyclotetrasiloxanes, dodecamethylcyclohexasiloxanes, and decamethylcyclopentasiloxanes. These are useful in various embodiments as substitutes for decacyclomethicone, or used in addition to it.
Similarly, other fatty acid esters are also useful in the present invention. Thus, esters of laurate, palmitate, stearate, arachidate, behenate, and lignocerate, or fatty acid esters containing an unsaturated bond, such as for example palmitoleate, oleate, linoleate, linolenate, and arachidonate are also useful in the invention as substitutes for myristate or used in addition to myristate. And fatty acid esters containing one or more unsaturated bonds are also contemplated in the invention, e.g., fatty acids containing one, two, or three unsaturated bonds such as linoleic, linolenic, palmitoleic, arachidoneic acids. Preferred esters for use in the invention include alkyl esters and alcohol esters. Preferred esters include isopropyl esters, methyl esters, ethyl esters, and propyl esters. The present invention also provides methods of killing lice, fleas, ticks, and other ectoparasites on a treated subject by topically administering to an area on the subject where the ectoparasites are present a compositions of one or more of these siloxanes. The siloxane is provided in an amount sufficient to kill ectoparasites present.
Other compounds can be included in the compositions of the present invention. For example sesquiterpenes (preferably S-methoprene), which kills the eggs of ectoparasites (e.g., lice and fleas), may be included to enhance the potency of the compositions by also killing eggs that may be present on the treated person. Addition of S-methoprene or another sesquiterpene or a juvenile hormone analog will aid the killing of eggs, therefore facilitating effective treatment and eliminating the need to treat the patient repeatedly. In preferred embodiments that contain a sesquiterpene, the composition contains the fatty acid ester and/or the siloxane, and the sesquiterpene, and does not contain any other agent in an amount sufficient for killing fleas or lice present. An acid may desirably be included in the formulation to assist in lowering the pH of the formulation, which will facilitate the removal of eggs that are cemented to hair or skin. The acids can be added to the formulations until the pH reaches about 4. Organic acids such as lactic acid, dilute acetic acid or glacial acetic acid, citric acid, are noninjurious acids that are useful for this purpose. Dilute hydrochloric acid can also be used. In other embodiments, the compositions contain no acids, or contain less than 1.0% acid.
The present inventors discovered unexpectedly that ivermectin is able to kill head lice and their eggs when topically applied. Thus, the present invention provides compositions and methods of treating ectoparasites (e.g., lice and fleas) by topically applying a composition containing ivermectin to the area to be treated. In one embodiment, the composition will contain ivermectin and will not contain any other agent in an amount sufficient for killing ectoparasites present. The person of ordinary skill in the art will realize that various compounds are available to act as carriers of the ivermectin. The ivermectin can also be included in any of the compositions of the present invention. For example, the ivermectin can be included in a composition with one or more of the fatty acid, the siloxane, and the sesquiterpene, and the composition will not contain any additional agent in an amount sufficient for killing ectoparasites present.
The present compositions and methods can also be useful for treating flea and tick infestations on household pets. Any mammalian pet may be treated using these methods (e.g., a dog or cat). The compositions spread evenly and with little effort, and dry quickly. Thus, they may be conveniently used with great effectiveness and little or no discomfort to the treated animal. The methods and compositions may also be used to treat ectoparasites such as fleas and ticks on domestic animals such as bovines, equines, porcines, ovines, etc. The person of ordinary skill in the art will realize that animals are primarily subject to flea and tick infestations but that porcines and other domestic animals are also subject to tick and lice infestations (known as Haematopinus spp.), and that the present compositions will be effective for both.
The present invention can also be useful for treating plant parasite infestations in plants and crops. The invention may be particularly useful in the context of a greenhouse, where individual plants may be treated with a composition of the present invention to destroy aphids, or other plant parasites such as, for example, white flies, spider mites, and other sucking insects. Other preferred applications include high value or ornamental plants, where undamaged foliage is of particular importance, or plants that bear fruit that is more desirable if undamaged. Such damage is frequently a result of applying chemical insecticides or pediculocides, which dry on the foliage, or is the result of the plant parasite activity. The methods involve topically applying a composition of the present invention to the plant to be treated. The compositions of the present invention have no detrimental affect on the treated plant. In various embodiments of the present invention, it may be desirable to utilize a composition containing a siloxane and a fatty acid ester as a carrier with the addition of other active compounds. For example, the siloxane and fatty acid ester composition may be useful as a carrier of fungicides, insecticides, or herbicides, because it possesses the desirable properties of drying quickly, spreading easily and evenly, and does not xe2x80x9cburnxe2x80x9d or otherwise cause damage to the crops, foliage, or fruit. Pesticides, specifically fungicides, herbicides, and insecticides that are not soluble in water can be applied advantageously using the present invention. For example, pyrethroids, organophosphates such as malathion and diazinon, pyrroles, or more generally azoles, glyphosate, nicotinoids, and triazines may be applied using a composition of the present invention.
In the context of application to livestock or domestic animals, the compositions contain no solvents that are irritating to the treated animals. Permethrin, macrolides such as ivermectin, doramectin, moxidectin, abamectin, emamectin, eprinomectin, mycins such as milbemycin, and fungicides such as the azoles can be applied with a siloxane and a fatty acid ester as the carrier and spreader. The azoles can include the imidazoles and the triazoles. The imidazoles include, for example, clotrimazole, miconazole, ketoconazole, econazole, and sulconazole. The triazoles include, for example, itraconazole and fluconazole.
In the compositions of the present invention a mixture of about 50% fatty acid ester and about 50% siloxane (w/w) is preferable. But the actual amounts of the ingredients may vary substantially. For example, the composition can also be at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% fatty acid ester, and the remainder the siloxane. Alternatively, the composition may be at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% siloxane and the remainder the fatty acid ester. Preferred amounts of the siloxane also include between 45% and 55% (w/w), between 40% and 60%, between 30% and 70%, between 25% and 70%, and between 35% and 65%. It is preferred that the fatty acid ester be present at less than 65% or 70% w/w and at more than 20%, 25%, or 35%, and most preferably at about 50%xc2x15% (w/w) or about 49.5% w/w. Other preferable amounts of the fatty acid ester include from about 40% to about 60% or from about 25% to 65% or between 45% and 55%, between 30% and 70%, between 35% and 65%, between 25% and 65%, or between 25% and 70% (w/w). Preferred amounts of the siloxane are between 25% and 75% or between 30% and 70% or between 35% and 65% or between 40% and 60% and most preferably at about 50% or 49.5%. In one embodiment the composition contains about 50% isopropyl myristate and about 50% siloxane and does not contain any other ingredients. In embodiments where additional ingredients are desired, such as S-methoprene, ivermectin, or a pesticide, these may be included in desired proportions while subtracting the siloxane and/or fatty acid ester accordingly. When S-methoprene is included in the composition, it may be present from about 0.02 % to about 2.0% or even higher, but preferably will be included at about 0.2% (w/w) or 0.4% (w/w) or 0.6% (w/w) or 0.8% (w/w). When ivermectin is included it may desirably be present from about 0.02% to about 1.0%, and preferably will be present at about 0.2%.
In other embodiments the fatty acid ester is present in the composition with a pharmaceutically acceptable carrier. While the siloxane is a preferred carrier because it spreads evenly, dries quickly, has low mammalian toxicity, and is believed to act synergistically with the fatty acid ester to kill ectoparasites, persons of ordinary skill in the art will realize that other pharmaceutically acceptable carriers are also useful. In these embodiments the fatty acid ester is used at the concentrations described above, with the rest of the composition being one or more carriers or other ingredients as desired.
The present invention also provides kits for treating ectoparasite infestations. In various embodiments the kits include a composition of the present invention in a package or other enclosure. In other embodiments the kits further include a xe2x80x9cnit combxe2x80x9d to assist in removing ectoparasites (e.g. lice) and their eggs from hair. The xe2x80x9cnit combxe2x80x9d is an ordinary comb for ordering hair by passing it through the hair. For example the LICEMEISTER(copyright) (National Pediculosis Association, Inc., Newton, Mass.), ACU-MED(copyright) Lice Comb (Health Enterprises, N. Attleboro, Mass.), MEDI-SWEEP Lice Comb (Classic Products, Oxnard, Calif.) are preferred embodiments of the lice comb to be included in the kit. The package can be a box, or may simply be a wrapping (preferably of a plastic) that surrounds the kit. The comb is preferably provided inside the package, but can also be attached to the outside of the package. In other embodiments the kits include markers such as fluorescent dyes or shower caps. In preferred embodiments the kit also contains instructions that describe how to use the items included in the kit to kill ectoparasites.